Stoke Therapeutics, Inc. (STOK) Q3 2026 Earnings Call Transcript

Operator: Good day, and thank you for standing by. Welcome to Stoke Therapeutics Third Quarter 2026 Business Update Conference Call. [Operator Instructions] Please be advised today's conference may be recorded. I will now hand the conference over to your first speaker for today, Thomas Leggett, Chief Financial Officer. Please go ahead, sir.

Thomas Leggett: Good evening, and welcome to Stoke Therapeutics Third Quarter 2026 Business Update Conference Call. I'm Thomas Leggett, the Chief Financial Officer at Stoke Therapeutics. Joining me on today's call are Ian Smith, our Chief Executive Officer; Dr. Barry Ticho, Chief Medical Officer; and Jason Hoitt, Chief Patient Officer. As a reminder, today's webcast presentation is available in the Investors section of our website. This webcast is being recorded and will be available for replay later this evening. Before we begin, please note that today's discussion includes forward-looking statements. These forward-looking statements are subject to risks and uncertainties, and actual results may differ materially. Please refer to our filings with the SEC for additional information. With that, I'll turn the call over to Ian.

Ian Smith: Thank you, Thomas, and thank you to everyone joining us this evening. It has been a busy quarter at Stoke. Tonight, we will discuss our recent progress, including an update on the advancement of patients through key time points in the EMPEROR Phase III registrational study of zorevunersen, our recent discussion with the FDA related to our NDA planning and the latest on our commercial readiness activities. I'll start with some highlights from our Phase III study. To date, approximately 110 of the 162 enrolled patients have completed their week 28 visit. This is the time point at which data for the primary endpoint of change in major motor seizure frequency is captured. Approximately 20 patients have also completed their week 52 visit, marking the end of the study treatment period and the time point at which key secondary endpoint data will be captured. All of these patients are continuing into the open-label portion of the study. Notably, there have been no treatment discontinuations to date. Barry will provide some additional metrics and context in a few moments. Next, I will highlight our recent interaction with the FDA that gave us the opportunity to discuss our 5 years of clinical data for zorevunersen, including our Phase I/II and OLE studies and to align on key aspects of our planned 2027 U.S. NDA submission. We were pleased with the agency's engagement, responsiveness, and interest in zorevunersen. An important outcome of our meeting was the FDA's willingness to accept a multicomponent assessment of Vineland-3 data for purposes of evaluating the key secondary endpoint related to changes in cognition and behavior. This is a positive outcome because we believe a multicomponent approach acknowledges the complexity of the disease and the fact that each patient's experience with Dravet syndrome is different, especially when it comes to impacts on cognition and behavior. Coming out of the discussion, we are reiterating our time lines for a data readout in Q3 2027, followed by a planned NDA submission in the second half of next year. Clarity on these time lines is important as we scale our organization and capabilities to deliver zorevunersen to patients following a potential U.S. approval in early 2028. Our medical affairs team has done an incredible job over the past 2 years, establishing a foundation of awareness and understanding of Dravet syndrome and the data to support the disease-modifying potential of zorevunersen. We are continuing to expand our educational efforts, moving to reach more clinicians and other stakeholders, including payers with the recent addition of our field market access team. We continue to learn as much as we can about Dravet syndrome and the opportunity through ongoing research. These efforts have given us additional confidence in the addressable patient population and are guiding our organizational build. At the same time, the field is continuing to evolve, and we see growing awareness of the needs of patients with Dravet syndrome and other genetic epilepsies. We are encouraged by the actions of stakeholder organizations such as American Epilepsy Society's Presidential Task Force on preparing for disease-modifying therapies and education and advocacy related to the need for genetic testing. Jason will share more on these efforts in a few minutes. We see haploinsufficiency diseases as a clear and unique opportunity for our platform, which is why we are excited to advance STK-002. Autosomal dominant optic atrophy or simply ADOA is a rare genetic disease that is primarily caused by a haploinsufficiency that results in 50% of functional protein production. STK-002 is designed to increase naturally occurring fully functional OPA1 protein production to address the underlying cause of this disease. In addition to our preclinical data, recent data from the field supports the potential of the OPA1 targeting hypothesis. Dosing is now underway in the third cohort of our Phase I OSPREY study, and we expect to initiate the fourth dose cohort in early 2027. Initial safety and efficacy data are anticipated in the first half of next year, which will inform future development. As we expand our research efforts, we will continue to focus on severe genetic diseases, driven by haploinsufficiency with an emphasis on the CNS given our experience in Dravet syndrome. With that, I would summarize by saying that Stoke has made great progress throughout 2026, and we are well positioned heading into the end of this year. With that, I will turn the call over to Barry.

Barry Ticho: Thank you, Ian. I'll start by expanding on our Phase III progress that Ian mentioned. EMPEROR is a global double-blind, sham-controlled Phase III study of zorevunersen in patients with Dravet syndrome. The study is designed as a 52-week treatment period in which patients receive 2 loading doses plus 2 maintenance doses of either zorevunersen or sham, followed by an open-label extension period in which all patients receive zorevunersen. The primary endpoint is percent change from baseline in log transformed major motor seizure frequency at week 28. All secondary endpoints are measured at week 52. To protect the integrity of the study, we will not review or analyze any data until all patients reach week 52. The study is progressing very well. All 162 patients enrolled in the U.S., U.K., and Japan are through week 8 of the study, which means that they have received either the 2 loading doses of 70 milligrams of zorevunersen or sham. Approximately 130 patients are through week 24 and, therefore, have only 1 of the 4 doses left in the 52-week treatment period. Approximately 110 patients have also completed their week 28 visit, the time point at which the primary endpoint of change in major motor seizure frequency is measured. Approximately 65 patients are through week 40 and have, therefore, received all 4 doses of zorevunersen or sham. Approximately 20 patients have reached the end of the 52-week treatment period. All of these patients are continuing into the open-label extension period. No patients have discontinued treatment in EMPEROR. When we originally designed EMPEROR, we set an enrollment target of 150 patients. This was based on a goal of 128 evaluable patients at the end of the study with an assumed 15% discontinuation rate. We ultimately enrolled 162 patients. And as I mentioned, there have been no discontinuations to date. These metrics reflect a well-designed trial, the need for better treatments, and a deeply committed community of investigators, site teams, and caregivers. The primary endpoint of EMPEROR is change in major motor seizure frequency at week 28. There's no doubt that antiseizure medicines are providing benefit for patients. Even still, seizure control remains the #1 goal for new treatments. Demonstrating a disease-modifying impact on cognition and behavior is expected to take longer, which accounts for the year-long treatment period and evaluation of the Vineland results at week 52. As Ian mentioned, for the purposes of our U.S. NDA, we plan to use a multicomponent assessment that combines 4 prespecified Vineland-3 subdomains: Expressive communication, receptive communication, interpersonal relationships, and personal skills. We believe the multicomponent assessment is the most appropriate way to evaluate changes in cognition and behavior due to the variability in how the disease affects patients. To generate a multicomponent score, we first calculate the individual treatment effect for each subdomain using a multivariate mixed model for repeat measures or MMRM. We then average all 4 scores to produce a single number that reflects the overall treatment effect. I'll show you what that looks like in a minute. Before I do that, I want to remind you of an analysis that we performed back in 2024 to inform the design of the Phase III study and specifically to help us prioritize the selection of Vineland Subdomains. On the left side, you see data from a subset of patients treated in our Phase I/II and OLE studies. These patients received a total cumulative dose of zorevunersen that was consistent with our plans for Phase III. On the right, you see data from patients followed in our natural history study whose baseline characteristics were matched in the treated patient population. Week 68 was used for these analyses because it was the most proximal to a 52-week study design when accounting for the pause in dosing between the last Phase I/II dose and the first OLE dose. Selection of these subdomains was further supported by feedback from clinicians and caregivers. Now with an additional 2 years of data and in light of our recent discussion with the FDA, we generated a multicomponent analysis using propensity score weighting to calculate a treatment effect. Use of propensity score weighting mimics randomization by adjusting for baseline differences between treated and natural history groups. This is the closest we can come to replicating a randomized trial. This analysis demonstrates the overall treatment effect across the 4 subdomains using a multicomponent average as well as the contributions of each of the 4 selected subdomains. Even with small numbers of patients, a highly statistically significant multicomponent score was demonstrated. With 5 years of clinical data, an assumption of 150 evaluable patients, and the change to a multicomponent assessment of the Vineland-3 for our U.S. NDA, we have run a calculation of the minimum treatment effect to achieve a p-value of 0.05 to 0.01. The study has 90% power to detect a treatment difference between treatment arms of 46% to 53% relative reduction in seizure frequency at a 2-sided significance level of 0.05 to 0.01, respectively, at weeks 28 and week 52. For the second key secondary endpoint measured by Vineland-3, the study has 90% power to detect a treatment difference of approximately 1.8 to 2.1 raw score points in the multicomponent assessment at week 52, using the same 2-sided significant levels of 0.05 to 0.01, respectively. We are often asked to explain the real-world meaning of these Vineland scores. What I can say is that even small changes can have meaningful impacts for patients and their families. This has been documented in the literature and is evident in the video case study that was included as supplemental to our data published in the New England Journal of Medicine earlier this year. We will continue to keep you updated as we progress the study, and we look forward to our data readout in Q3 of next year. Let me turn to our second clinical stage program, STK-002. Momentum and awareness of this program are increasing. Earlier this month, at the American Academy of Ophthalmology Annual Meeting, our team has delivered 2 presentations of data that support the potential of STK-002 as a disease-modifying treatment for ADOA. ADOA is a rare genetic disease that leads to progressive degeneration of the optic nerve and vision loss starting in the first decade of life. It is the most common inherited optic nerve disorder, affecting approximately 13,000 in the U.S., U.K., EU4 and Denmark. The majority of cases are caused by mutations in one copy of the OPA1 gene, resulting in haploinsufficiency and reduced functional OPA1 protein. Approximately half of people living with ADOA will progress to legal blindness. There are currently no approved treatments for ADOA. STK-002 is designed to increase OPA1 protein expression with the aim of improving vision in people with ADOA. We are encouraged by our preclinical data as well as emerging data from the field, demonstrating that upregulation of OPA1 protein has disease-modifying potential. In ADOA patient-derived cells with different OPA1 variants, STK-002 significantly increased OPA1 protein expression and improved mitochondrial function compared with healthy controls. On the next slide, you see that after a single intravitreal dose in nonhuman primates, STK-002 was also shown to reach retinal ganglion cells and increase retinal OPA1 protein. On the left side, staining shows STK-002 in red in retinal ganglion cells with increased signal correlating with increased dose. In the center, immunofluorescence staining with an OPA1 antibody, again in red, shows an increase in OPA1 protein in the retinal ganglion cell layer. OPA1 protein levels increased at all doses by week 4 by 44% to 47% at the 0.3 milligram and 1 milligram doses, respectively. The Phase I OSPREY study in people with ADOA is ongoing in the U.K. and Europe. The study aims primarily to evaluate the safety, tolerability and exposure of single ascending doses of STK-002 following a standard dose escalation design. OSPREY will also assess clinical activity, including changes in visual function and patient quality of life as well as retinal mitochondrial dysfunction. Data from our natural history study show higher levels of mitochondrial stress strongly correlate with decreased visual acuity. OSPREY is designed to provide clinical proof of concept by testing whether increasing OPA1 protein expression with STK-002 translates into measurable effects on visual function in patients with ADOA. The study is progressing well. We recently completed dosing of the first 2 cohorts of patients and dosing in the third cohort is underway with completion expected by year-end. Subject to ongoing safety assessment, we expect to begin dosing of the fourth cohort in early 2027. We expect cohorts 3 and 4 to reach dose levels that may produce measurable effects on visual function. Initial safety and efficacy data from these higher dose cohorts are expected in the first half of 2027. With that, I will turn the call over to Jason.

Jason Hoitt: Thank you, Barry. Shifting back to Dravet, I'll start by sharing an overview of the patient population. While we've shared these data previously, our latest market research continues to validate our assumptions and strengthen our confidence in the numbers. There are an estimated 38,000 patients with Dravet syndrome across the 7 major markets where we're running the EMPEROR study, the U.S., U.K., EU4, and Japan, including approximately 16,000 in the U.S. alone. Of those 16,000 in the U.S., we estimate 6,000 are under the age of 25 and likely under the care of a pediatric provider. These are the patients who would be immediately addressable at the time of a potential U.S. launch. Pediatric neurologists and epileptologists tend to follow the field closely and are typically the most well informed about the disease and current treatment options. An ICD-10 code was established in 2020 and is used to track confirmed Dravet diagnoses. With the increasing awareness of Dravet syndrome and the importance of genetic testing, we're seeing 40 to 50 new patients entering these claims databases every month, equating to 500 to 600 every year, including newly identified younger patients and older patients finally arriving at a diagnosis. As a result, we anticipate the total number of immediately addressable patients to increase between now and the time of launch. We're confident that we know where 80% of the 6,000 immediately addressable patients are being cared for today. In the U.S., the Dravet population is highly concentrated around centers of excellence and other key treatment centers. Approximately half of identified U.S. patients are cared for by the top 50 sites. All 50 of those sites are experienced in administering intrathecal medicines and over half of these sites have participated in a zorevunersen study. There's a high level of awareness of zorevunersen in anticipation for the Phase III readout and potential approval. The Dravet community has been involved in this program since its earliest days and sites are anticipating strong demand upon the potential U.S. approval. Several of the top treatment centers have proactively reached out to us asking what they can do to be ready to deliver zorevunersen. Our teams are beginning to engage with sites to help them prepare the infrastructure, protocols, and staff expertise necessary to administer zorevunersen with appropriate capacity. The Dravet community has been waiting years for a medicine like zorevunersen. Our job is to do everything we can to ensure they don't have to wait a day longer than they need to. To that end, we're adding resources and capabilities with an emphasis on people who have launched high science new medicines, particularly for rare genetic diseases and are committed to delivering excellence in patient care and overall experience. Our head of patient services recently joined Stoke, and she's in the initial stages of designing a patient support program that reflects the unique needs of this patient community and enables timely access. Our goal is to make the process between prescription and treatment as simple and easy as possible. Co-creation sessions with caregivers, clinicians and office administrators are underway to design a program that meets their needs. On the payer side, we recently deployed our payer account team who will start their educational efforts with medical directors at insurers across the country. These educational efforts build upon the years-long effort of our medical affairs team, who have supported our clinical teams and have done an exceptional job of education and awareness with health care providers and treating physicians around the world. Our latest HCP market research shows a high conviction in the data and in the disease-modifying potential of zorevunersen. We're also making progress among the broader neurology community who may be less familiar with the latest advances in the treatment of Dravet syndrome. We are very encouraged by the growing awareness and interest we experienced at the recent Child Neurology Society meeting. As recently as 3 years ago, very few people at this meeting knew about Dravet, zorevunersen, or Stoke. Today there's a far greater appreciation among general neurologists and epileptologists for the genetic drivers of Dravet syndrome and the reclassification of genetic epilepsies as DEEs. The ability to genetically diagnose these diseases is also prompting physicians and medical societies to rethink the treatment paradigm. One such example is the American Epilepsy Society's new Presidential Task Force on disease-modifying therapies. The intent behind this new initiative is to prepare those who treat these diseases for the arrival of genetically targeted treatments. We're encouraged by initiatives like this one, which complement the work we're doing, signaling a shared commitment to improve outcomes for patients and recognition of the potential for a new class of medicines. Beyond our educational efforts, we're preparing to initiate 2 additional clinical studies of zorevunersen by the end of this year. This includes a study in adult patients, which is intended to support access and reimbursement as well as a study in infants and toddlers. The primary objective of these studies is to evaluate the safety of zorevunersen in these populations. These are not registrational studies. Consistent with our breakthrough therapy designation, we believe we can achieve a broad label without an upper age limit. Taken together, the strength of the clinical package, the continued positive feedback from payers and providers and how we're preparing our organization and the treating community give us confidence that we'll be able to deliver zorevunersen to families quickly at the time of a potential U.S. launch in early 2028. With that, I'll turn it over to Thomas.

Thomas Leggett: Thank you, Jason. I will remind you that full financial results can be found in today's press release and our 10-Q that will be filed next week. Today I will focus on the strength of our balance sheet position. We ended the quarter with $358.8 million in cash, cash equivalents, and marketable securities. This excludes restricted cash of $3.2 million. Our net loss for the 3 months ended September 30 was $73.6 million, which includes $11 million of noncash stock-based compensation expense. Our priorities at Stoke have not changed, advancing our Phase III study of zorevunersen, preparing the organization for potential U.S. commercialization, and investing in our pipeline while maintaining a strong financial position. Along with the reimbursement we received from Biogen for zorevunersen-related expenses and a potential development milestone payment, we expect our cash position to fund our operations into early 2028. Thank you. I will now ask for the line to be open for Q&A.

Operator: [Operator Instructions] And our first question is coming from the line of Kevin Strang with Goldman Sachs.

Kevin Strang: Just a question on the design for EMPEROR in terms of data quality monitoring. Can you walk us through how you design the trial with that in mind in terms of the Vineland-3 subdomains scores? How you could consistently collect that across different time points across different sites? That would be helpful. And then just a brief follow-up on the multicomponent analysis plan that you have in place now. Are there any meaningful differences between this plan with the FDA and what you have planned in Europe?

Barry Ticho: Thanks, Kevin, for the question. This is Barry. So the collection of the data for the Vineland study is vitally important. And so what we have put into place are several measures. One important one is that there is a trained central rater who collects all the data and puts together the scores, so that is uniformity across all the different sites. Second is that we encourage the same family member to be the reporter on the questionnaire. So at every time that the questionnaire is asked, it's the same person giving the response. And then we also do have an internal spokesperson who is reviewing on nearly a daily basis to make sure that the Vineland tests are being collected and done appropriately at every site.

Ian Smith: Kevin, it's Ian here. I'll take the U.S. versus Europe question. Correct, and I'm sure we'll talk about more on this call, the MC4 as we call it now. That's for the U.S. But in Europe, they still have what's called a net treatment benefit for individual Vineland subdomains, and there's 5 of them in a similar way that we had before we got to the MC4. Biogen is in control of that filing in Europe, and we'll wait to see how they proceed with those authorities overseas.

Operator: Our next question in queue coming from the line of Laura Chico with Wedbush.

Laura Chico: Just 2 for me. I guess following the interactions with FDA, I'm wondering if you could elaborate if there's been any change on the potential for an advisory committee meeting. How have the expectations there changed? And just a point of clarification, what remaining areas need to be resolved prior to the rolling submission? And I'm sorry, one last one for Barry, perhaps. You recently presented some data at the CNS meeting on the OLE data. Could you just remind us on how the protocol there handles discontinuations of pre-existing ASMs? I guess maybe said it differently, I'm trying to remember whether patients are coming off some of their baseline ASMs when they were -- what they were on at study entry.

Ian Smith: So Laura, I'll take the first 2, and then Barry can take the question regarding maybe a change in medicines or ASM medicines through to week 28. And so firstly, AdCom, we don't anticipate an AdCom. There was absolutely no discussion relating to an AdCom when we had our FDA interaction a month or so ago. As far as submitting data for the NDA, we anticipate submitting data throughout the first half of 2027 with a completion of the submission in the second half of 2027. And what we want to do is we want to submit that data to give the FDA the option to review early. There's no guarantees they will review early until they actually confirm that they're doing a rolling review. And so we will await that, but we will be submitting the data to the FDA to give them the option. And we'll be continuing to work with the FDA to talk about the importance of what our medicine has shown basically through our Phase I/II and our OLE data. And we've had multiple meetings outside just this meeting with the FDA to show the importance of our data and the urgent need to move fast through our submission and potentially through our approval. And Barry, do you want to talk about how we treat the change in ASM medicines through week 28?

Barry Ticho: Sure. Thanks, Laura, for the question. So the background antiseizure medications, the patients are monitored for the first 6 weeks before treatment with the background antiseizure medications kept stable. And then they are supposed to stay stable through at least the first 6 months to the week 28 endpoint. And again, the background medications are continued. So any effects that we're going to see with zorevunersen will be on top of the baseline antiseizure medications that they're already on. This is the way we saw in Phase I/II that the improvement that we saw in terms of -- or the reductions that we saw in seizures, seizure frequency were on top of background standard of care antiseizure medications.

Ian Smith: Laura, could I just also add, it's a great question, one actually Barry and I frequently talk about. And that I want to remind everyone that there is an 8-week screen period before you come into the EMPEROR study. That 8-week screen period, there's a number of things. But one of the things it does is it allows you to assess that these patients are already on a stable background of medicines. And so when they enter the study, whether they go into sham or active drug arm, they're on a stable background of antiseizure medicine. So we would anticipate there to be small changes in terms of antiseizure medicines. And -- but there probably will be changes. And we will assess week 28, and we'll look at the data with and without the changes with those background seizure medicines.

Operator: Our next question in queue coming from the line of Pete Stavropoulos with Cantor Fitzgerald.

Pete Stavropoulos: Congrats on the progress. A couple for me. For the Vineland-3 subdomains, you showed a very impressive forest plot compared to natural history. You mentioned on the call that even small changes can be meaningful. Just help us understand what those treatment effects sort of translate to with examples. Also -- that was also at 18 months. What gives you confidence that the 1-year time point is sufficient to cap the differences between the 2 different arms under the current multicomponent assessment of the 4 prespecified subdomains.

Barry Ticho: Pete, this is Barry. Thanks for that question. Very important. So when we look at the treatment effect of the Vineland changes, we know that even small changes can be -- reflect an impactful -- an impact on the families. And we've heard that from many families. The measures of the Vineland are scores of 0, 1, and 2, for instance. And the -- so that means that a score of 0 would mean for a particular activity, that child would never do that. And a score of 1 would be usually. So if you ask a question, for instance, does the child respond to their own name or be able to say their own name. Those are questions. If you can imagine a child never being able to say their own name as opposed to sometimes being able to say their own name. That's a change of one point, which, as you can imagine, is quite meaningful for a family. Another would be following a simple instruction of one action. Again, 0 being they never can do that or 1 being they can. So as you can imagine, these are effects that are having a huge impact, both on the quality of life of the child as well as the family.

Ian Smith: Pete, I'll just add to that. This -- I'm not sure how familiar people are with Vineland-3. To be honest, it sits on my desk. I look at it most days of the week, and I look at the questions. And as Barry gives some good examples. But it also includes things like, do you recognize your name? Never, you get a 0. Sometimes you get a 1. Usually, you get a 2. And that's how it works. And there's a long list of these type of questions that you add up in terms of a total score at baseline. You then do it at week 52 in our study and same questions and you add it all up. And let's say there's a total score of 150, but then at baseline, but then you get a total score of 154. That would be 4 Vineland points, 4 extra points. That would be what -- maybe the drug is contributing towards. So that's how the scoring works. And so to Barry's point, you shift somebody that never does something to a patient that does something sometimes, that's a 1-point score and, therefore, meaningful. And I would advise people to take a look at the Vineland scoring or the questions, and you'll get a good feel for the type of questions that are asked. As far as your question regarding the 12 month, and so yes, we did put up the forest plot for the 18-month data. Interestingly, what we're trying to show here is that -- I would start with saying, when you take the basket of endpoints approach, you have multiple ways to measure disease modification. And contrast that to a hierarchical assessment of individual Vineland domains. There is sometimes a little bit of a lottery there if you can hit the first one, so you can go to the second one and hit the second one to go to the third one. With the multicomponent assessment, we removed that hierarchical assessment, the need for hierarchical assessment. And what you're doing is you're assessing 4 domains equally as a basket to get an average score. And that's a much better way in a disease that manifests itself with multiple comorbidities that, frankly, do manifest at different variations within each patient. What it also does, which is a really nice outcome, it's a statistical outcome. But because you've got more evaluable data, you're measuring an endpoint 4x, you actually get more powering. And you asked about the 12-month data and scoring, if we ran the same assessment, we did. And interestingly, in those 4 domains, we missed p-values on 3 out of the 4, but we hit 1 out of the 4. Overall, our MC4 score, so our multicomponent score achieved an overall p-value of less than 0.001. Just to give you an idea of how much it enhances the powering because you've got more evaluable data and you're assessing 4 endpoints equally. Now those 3 endpoints that missed, they did have trends and they were close to 0.05. So understand that. And there was one that was below 0.05. But overall, the MC4 p-value was 0.001 or 0.01, sorry, so less than. And so what we're trying to show here is that we've enhanced the powering of the study. But as a principle, it's enhanced and it's more appropriate of how to measure the cognition and behavioral benefits our medicine may be providing to these patients because it is a basket approach.

Pete Stavropoulos: Congratulations again on the progress and looking forward to the data.

Operator: Our next question coming from the line of Andrew Tsai with Jefferies.

John Cox: Congrats on all the great execution. This is John on for Andrew. So earlier this week, your partner, Biogen, made a comment about how they think differentiation and differential pricing, especially for ex U.S. is for zorevunersen to have an impact on cognition. So just curious how you guys think about their comments and whether there is an alignment on the underlying value proposition.

Ian Smith: Well, I think Biogen can give you their best answer. And so I don't mean to speak for Biogen. But I've been involved with rare disease, genetic diseases, and readouts in the single-payer markets within Europe, for example, which is what I think you're asking about, John. I will tell you that it is more challenging in those markets than it is in the U.S. And in the U.S., I would say the approach -- and we're very comfortable talking about the U.S. because that's our -- those are our territories. But in the U.S., it is about the totality of the data. And we've been sharing 4-year OLE data, New England Journal of Medicine, various peer-reviewed presentations with the payers, and they understand the value of the medicine, and Jason will probably comment on that later. Whereas in the EU, for example, they do hold you closer to the label in terms of valuing the medicine. And they have a whole scoring system in certain countries. But overall, it is more challenging over there. But Biogen should be able to provide you more understanding of that. But it is more challenging in Europe.

John Cox: And then maybe just one quick follow-up, if I may. I was curious, like besides the Vineland-3 adjustment in the recent FDA meeting, what other topics may have come up in the meeting with the FDA? Or was Vineland 3 kind of the main focus?

Ian Smith: There was a few other things. I think Vineland-3 getting to the multicomponent 4 assessment was the priority focus. The submission of data to the NDA was important. And there was also -- we did ask the question regarding the OLE data, the 4-year OLE data, which will be 5-year OLE data by the time that we submit our data. We asked them whether that can be included in the label. And we've got a clear answer from them, which is it will be a review issue, which is a good answer for us and this is a chronically dosed medicine. And by the time we file, we're going to have 5 years' worth of data to show how these children may have compounded benefits year 1 to year 2 to year 3 to year 4 to year 5. And we believe that's important. And the regulations for labeling is that you put clinical study data on the label that is supportive of an understanding of the benefits that a medicine may provide. Overall, the interaction with the FDA is always a great opportunity to continue to educate on our medicine. And that's where we started with the OLE data because it is a chronic disease and that we're dosing a chronic medicine. And we've come a long way with the FDA over the last 2 years. And I think that was one of the reasons that drove the outcome to the multicomponent assessment where we're assessing cognition and behavior on a basket of endpoints now.

Operator: Our next question in queue coming from the line of Sumant Kulkarni with Canaccord.

Sumant Kulkarni: This is again related to the Vineland scale and the multicomponent assessment used as a key secondary endpoint. Does the relative contribution of a subdomain to the average score assume importance? And would high deviations from the mean on subdomains make a difference to being able to support a disease-modifying claim on the label? I guess asked another way, would an average that meets the definition of clinical relevance still be viewed that way if 1 or 2 subdomains drive most of the difference even if the others may take away from the effect?

Ian Smith: Thanks for the question, Sumant. The way it does work, and I'll keep it simple, which is you do assess equally each subdomain. So there's 4 subdomains you assess equally. Let's say, you score a 3, 3, 2, and 2, make the numbers easy. Divide that by 4, and that gives you a multiple -- MC4 score of 2.5. That's what you then assess the p-value. One of the things I want to be very clear on what we're trying to help you with these forest plots that we've showed today, that 2.5, if you score it, because you're assessing Vineland 4 different ways and you've got more evaluable data, you get more power to that score. And that's why when I referred to the 12-month or even the 18-month scoring of MC4 that we've got a lower p-value than we did in any individual domain. And so what it really translates to is you could miss on one of the domains in terms of a p-value, but still achieve a significantly low p-value of potentially 0.01 as we saw on the 12-month data. And I'll just take this opportunity, when I say we missed on 1 on the 12-month data, I want to be clear, and Barry was in his remarks earlier on this call, the 12-month data was suboptimal dose. There was a 6- to 7-month gap in dosing, and they did not get the level of dosing that we're dosing in our Phase III. So I do want to remind people of that. But I'm giving you the example, we still hit a very low p-value, less than 0.01 even on the 12-month data. So it is a simple kind of average. But because you've got more evaluable data, you get greater powering.

Barry Ticho: And I'll just add to that, this is Barry. So what Ian was talking about also that the 12-month data, those are a relatively small number of patients, quite a small number of patients. So obviously, we're going to have more. Addressing your question a little bit more specifically, there is no -- of the 4 subdomains, there is no one that is more important than the other when we do this calculation. And the other thing that the advantage of doing this multicomponent is that it smooths out the variability and the differences between different subdomains. So even if there is one that is extreme, extremely high, for instance, or extremely low, the multicomponent will take that into account and average it out.

Operator: Our next question coming from the line of Yaron Werber with TD Cowen.

Yaron Werber: Really nice progress. So Barry, on the last point on the MMRM is a big deal on the composite, right? Because essentially, it uses the entire curve in every visit, you're not just doing baseline against the end. And as you mentioned, it really helps reduce heterogeneity and ultimately really boost the power. And also I believe that when you use MMRM, you're not -- the way you handle dropouts is you don't have to infuse. Can you comment on that? And also the second question, are you doing the MMRM multiplicity at the same time? Or is each score still hierarchical of the 4 domains?

Barry Ticho: This is Barry. So as far as the MMRM, yes, we're using the MMRM for the Vineland. And the advantage of that is that it takes into account all of the data collected up to that time point. So as you mentioned, it's not just at week 52. So we do have a collection of the Vineland, for instance, at 6 months in the study. So that would be combined with the data that we have at the 52-week endpoint. And it does allow then for any missing data and could then impute for missing data or take that into account. As far as the hierarchy, the multicomponent endpoint will be assessed as all 4 of the subdomains together. And so there is no need to put together any hierarchy, and that was part of what we had an agreement with FDA that we can measure, just add the key, the second key endpoint. We will just use the multicomponent and not have to do any ranking of the subdomains. So that obviously is an advantage in terms of having power for that endpoint.

Operator: Our next question in queue coming from the line of Joseph Stringer with Needham.

Joseph Stringer: Just a follow-up question on the statistical analysis. Just given the change to the MC4R analysis from the individual component, can you speak to how this affects the alpha allocation? Does this change the split across the primary endpoint, the week 28 endpoint, and the seizure endpoint at week 52 in this new MC4 -- excuse me, MC4 assessment?

Ian Smith: So Joe, it's Ian. I think Barry referred to these endpoints and how they're measured, the primary, given this change with MC4. We -- in the prepared remarks, we gave you the updated powering. And so let me just remind you of that. Firstly, we do have more patients that are being retained in this study than we initially anticipated. Just to remind you of the initial expectations, we thought this would be a 150-patient study with potentially a 15% dropout. That gave you as an estimate of needing 128 patients to power the study. We bring it all the way forward, as of today, we've got 162 patients in the study, of which 0 dropouts and 110 of those are already through the primary endpoint. So we believe there is going to be more evaluable patients. And what we showed you today is we're making an assumption, that's all it is, but maybe there's going to be 150 evaluable patients. Assuming there's 150 evaluable patients and with this new assessments, we anticipate that we need a 46% to 53% treatment effect for seizure reductions just to achieve p-values of 0.05 or 0.01. And for that Vineland endpoint, it's now 1.8 to 2.1 to achieve a p-value of 0.05 to 0.01. So it is -- the evaluable patients that are still in the study and this change has really enhanced the overall powering of the study. But I do want to continue to kind of echo, I'll say, or repeat, the real benefit here is this is a disease with many comorbidities. And they evolve at different rates within different patients. And so being able to measure these endpoints in a basket approach is the real win here because that's the way you should be measuring disease modification.

Barry Ticho: And I'll just add, Joe, to your question. In terms of split, there is no alpha split. So the seizure reduction at 28 weeks is the primary endpoint. 52-week seizure reduction is the first secondary and the Vineland is the second secondary. And so alpha is not split between those.

Operator: Our next question in queue coming from the line of Jessica Fye with JPMorgan.

Jessica Fye: I was curious, what do experts tell you is a clinically meaningful drop in seizures?

Ian Smith: Clinically meaningful drop in seizures. Actually, Jason, why don't you take that? You spend a lot of time in the field.

Jason Hoitt: Yes. It's a great question, Jess. When we talk to health care providers and market research, I think the first thing they talk about when you talk about what the unmet need is in Dravet, it is the persistent seizure burden that exists today with the antiseizure medicines. And the desire, the strong desire to ultimately get as close as possible, if not to seizure freedom itself. And so any additional reduction in seizures on top of the best standard of care medicines is considered in advance. But I think most are expecting something in the neighborhood of 40% to 50% additional reduction over what you would see in the control arm.

Jessica Fye: And to be clear, is that an expectation for the trial? Or is the threshold for clinical meaningfulness really 40%?

Jason Hoitt: It's more what their expectation is of a disease-modifying treatment versus clinically meaningful. I think if you ask them what's clinically meaningful, fewer seizures is always clinically meaningful relative to more seizures.

Jessica Fye: And just last one for me. Is success in EMPEROR defined by achieving stat sig with a p-value less than 0.05 or less than 0.01?

Barry Ticho: This is Barry. Yes, the answer is 0.05. So this is a standard assessment that we have put into the protocol so that 0.05 for the primary as well as the key secondaries would be statistically significant.

Operator: Our next question coming from the line of Marc Goodman with Leerink.

Marc Goodman: Did the comment around the 5-year data being a review issue, did that refer to if the study just misses, then the FDA would consider the longer-term 5-year data a review issue? Is that what you were saying?

Ian Smith: When it comes to misses, it always depends on how close you are on the miss, and it's always a discussion. I mean there's many drugs that have p-values that miss on the 0.05, would have been close. And when you take into the totality of the primary and secondary endpoints and tertiary endpoints, you can absolutely have a discussion with the FDA. I do feel as though we're in a good position with the OLE data, which will be 5 years of OLE data or effectively 6 years of OLE data by the time we file. And so it does put you in a good position. But we didn't discuss -- Marc, we didn't discuss with them about missing. It was more of an education of the disease, and we started that just as we did this time last year when we asked if they would support an NDA submission on the basis of the OLE and Phase I data. And this continuous education certainly over the last 2 years has really brought the FDA forward to be in a real good spot of understanding the disease and how our medicine affects that disease. And so it will be the totality of the data that will drive the label.

Marc Goodman: I guess, Ian, one of the other analysts was asking about, at the FDA meeting, and you mentioned 3 things, and the third thing was they asked about the 4-year data and you talked about the 5-year data, and you said it was a review issue. What did you mean exactly when you said it would be a review issue, referring to the 5-year data serving as what?

Ian Smith: Okay. Yes. Thanks for clarifying, Marc. So when you go to the FDA, the process is you submit a briefing book, that briefing book has questions in it. One of the questions that we put in that briefing book specifically was, would you support putting the OLE data within our label, Section 14 is known as, but would you support putting that data in our label if we would have to have approval? And as you probably know, the FDA doesn't say yes at this point in time, but they did say it would be a review issue, which is a very clear answer, which is the totality of data. And so that's what I meant by it be a review issue.

Marc Goodman: And then just secondly, just to be clear on this MC4, it can be positive even if the benefit is concentrated in 1 or 2 subdomains the way you've described it, right? So that discussion is, you've had that with the FDA. Like it's -- if you hit your Vineland secondary endpoint with the p-value, you're going to be good, right, even if it's driven by 1 or 2 of these subdomains. Is that fair to say?

Ian Smith: That is correct. They've actually gone as far with us in the discussion to advise us that they would like to see it as a forest plot because they want to understand what drives the MC4 score. So the example you just gave, Marc, is a good one where you make the example where you say you miss or you get a 0 in one of the domains. But if you hit on the others, yes, as long as you hit your p-value on MC4, yes, acceptable.

Operator: Our next question in queue coming from the line of Rudy Li with Wolfe Research.

Guofang Li: Maybe a question for Barry. For upcoming ADOA readout in first half, so what is the bar for visual retinal benefit to support your dosing selection? I mean, making sure you're reaching the therapeutic levels. Are you measuring OPA1 protein levels? And do you need further dose-ranging study before pivotal?

Barry Ticho: Rudy, thanks for the question. So the ADOA program is a very important program for us. And we do have quite a bit of preclinical data and data from the field that supports the premise that increasing OPA1 protein levels in the cell can have a beneficial effect and potentially even improve vision in ADOA patients. So the Phase I study is designed primarily as a safety study, which will be an important readout. But we are also looking at visual acuity as well as a biomarker measure of mitochondrial function. So those will be important endpoints for us to analyze in terms of the decision to make to go forward. But again, improvement in vision would be something that we would be looking for as well as the safety effects.

Guofang Li: So it sounds like you need another dose-ranging study to determine the right dose moving forward. Is that fair?

Barry Ticho: I would say that we'll wait and see what the data are. We are considering different ways to potentially accelerate the program because this is a disease where the patients -- there is no approved medicine for this patient. And these patients are progressively losing vision. And so there's a tremendous amount of interest, both on the part of the patient advocates as well as the clinicians to see this sort of medicine. So we're going to look for the way that we can most quickly get the medicine to the patients. And to your other question, in terms of the OPA1 protein level, that's not something we're measuring. But as I mentioned, we have this biomarker for mitochondrial function. So that would be an important way that we could look at the basis for the mechanism of action of the medicine.

Operator: Our next question coming from the line of Yatin Suneja with Guggenheim.

Yatin Suneja: Maybe just one more on ADOA. Could you maybe articulate for us a little bit more on what the learnings were from the first 2 cohorts? And then how would you characterize sort of like the concept later this year? So that's the first part. And the second is on the spend side. Could you maybe also comment on how should I model the spend in 4Q and in 2027? Any sort of color you guys could provide would be great.

Barry Ticho: Yatin, thanks for that important question. This is Barry. In terms of progressing the study, as I mentioned before, the primary endpoint is safety. We do have a safety monitoring committee that reviews the results, and they did review the results of the first 2 cohorts. And so that recommendation to move forward to the third cohort was part of the safety review.

Ian Smith: I'd just add, Yatin, to what Barry is saying, as we move into the third and fourth cohort at doses of 0.3 milligrams and 0.5 milligrams, we are starting to move into the therapeutic dosing level. And that's why we anticipate seeing safety and efficacy results in the first half of 2027. And Tommy?

Thomas Leggett: And Yatin, this is Tommy here. Thanks for the question. Just to help you -- just to get you straight there in terms of how to guide forward to Q4 2026, I think you should look at Q3 2026, you saw the increase, we saw quarter-to-quarter, and I think you could assume a similar number going forward.

Operator: I'm showing no further questions. I will now turn the call back over to Ian Smith for any closing comments.

Ian Smith: Thank you. Just want to thank everybody for their time tonight. We approached this call, thank you for submitting questions to us beforehand. It gives us good clarity. Fortunately, we were in position to help you understand this technical analysis of the primary and secondary endpoints and the powering of the study. All very important and all very good questions. So we appreciate your time and your patience of listening to us and look forward to catching up with you very soon. Thank you.

Operator: Ladies and gentlemen, that does conclude our conference for today. Thank you for your participation. You may now disconnect.